Quinoline inhibitors of cGMP phosphodiesterase

ABSTRACT

Compounds of the formula (I)  
                 
are useful as inhibitors of cGMP PDE especially Type 5.

RELATED INVENTIONS

This application is a divisional application claiming priority from U.S.Ser. No. 11/018,968, filed on Dec. 21, 2004 and allowed on Sep. 13,2006, which is a divisional application of U.S. Ser. No. 10/412,969,filed on Apr. 14, 2003, now U.S. Pat. No. 6,835,737, which is a divisionof U.S. Ser. No. 09/933,066, filed on Aug. 20, 2001, now U.S. Pat. No.6,576,644, which claims priority from Provisional Application No.60/230,267, filed on Sep. 6, 2000, all of which are included in theirentirety by reference herein.

FIELD OF THE INVENTION

The present invention relates to quinoline compounds, to methods ofusing such compounds in treating cGMP-associated conditions such aserectile dysfunction, and to pharmaceutical compositions containing suchcompounds.

BACKGROUND OF THE INVENTION

Erectile dysfunction is the inability to obtain and maintain a penileerection sufficient for sexual intercourse or other sexual expression. Anumber of factors can place an individual at risk for this disorder, forexample, trauma, pelvic surgery, hypercholesterolemia, ischemic heartdisease, peripheral vascular disease, chronic renal failure, diabetes,the use of certain medicarnents including some types of antihypertensiveagents, digoxin, or the excessive use of narcotics, alcohol, tobacco,etc. Methods for treating erectile dysfunction include the use of vacuumdevices and penile implants, as well as the administration ofmedicaments such as yohimbine, papaverine and apomorphine. Improvedmethods for treating this disorder are sought, however, as theaforementioned methods do not provide sufficient efficacy and/or areaccompanied by drawbacks or side effects such as erosion, pain,priapism, or gastrointestinal discomfort.

A penile erection is dependent upon the presence of adequate levels ofcyclic guanosine 3′,5′-monophosphate (cGMP), especially in corporacavemosa tissue. Thus, administering an inhibitor of a cGMPphosphodiesterase (cGMP PDE), particularly a selective inhibitor of cGMPPDE Type 5 (PDE 5), provides a means for achieving and maintaining anerection and therefore, for treating erectile dysfunction. SeeTrigo-Rocha et al., “Nitric Oxide and cGMP: Mediators of PelvicNerve-Stimulated Erection in Dogs,” Am. J. Physiol., Vol. 264 (February1993); Bowman et al., “Cyclic GMP Mediates Neurogenic Relaxation in theBovine Retractor Penis Muscle,” Br. J. Pharmac., 81, 665-674 (1984); andRajfer et al., “Nitric Oxide as a Mediator of Relaxation of the CorpusCavemosum in Response to Nonadrenergic, NoncholinergicNeurotransmission,” New England J. Med., 326, 2, 90-94 (January 1992).Sildenafil, for example, has been described as a PDE 5 inhibitor usefulfor treating erectile dysfunction. See Drugs of the Future, 22, 138-143(1997).

Recent examples of other compounds claimed as PDE 5 inhibitors includefused pyridazine compounds (WO 96/05176 and U.S. patent application Ser.No. 09/393,833), anthranilic acid derivatives (U.S. Pat. No. 5,716,993),fused pyridopyridazine compounds (U.S. patent application Ser. No.09/526,162), and quinazolinone compounds (U.S. Pat. No. 6,087,368). Thepresent invention provides compounds that are potent and selectiveinhibitors of cGMP PDE 5. These compounds may be employed in treatingerectile dysfunction. In view of their activity, these compounds canalso be used in treating other disorders responding to the inhibition ofcGMP PDE, such as various cardiovascular disorders.

SUMMARY OF THE INVENTION

The present invention provides quinoline compounds of the followingformula (I) or salts thereof, for use as inhibitors of cGMP PDE,especially Type 5:

wherein:

-   R₂, R₆, R₇ and R₈ are independently hydrogen, halogen, alkyl,    substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, or    heterocyclo;-   R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;-   R₄ and R₅ (i) are independently hydrogen, alkyl, substituted alkyl,    cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the    proviso that R₄ and R₅ are not both hydrogen; or (ii) taken together    form a heterocyclo ring;-   Y is selected (i) independently from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,    —O(C═O)NR¹⁰R₁₁, —NR₁₀R₁₁, —NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR¹⁰R₁₁]₂,    —(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂, —S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole,    substituted imidazole, triazole, substituted triazole, or cyano,    or (ii) together with one of R₄ and R₅ to form a heterocylo ring    therewith;-   m is 0, 1, or 2;-   R₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,    cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl,    or pentafluorophenyl; and-   R₁₀, R₁₁, and R₁₂ (i) are independently selected from hydrogen,    alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted    cycloalkyl, aryl, heterocyclo, and heteroaryl; or (ii) taken    together, wherein R₁₀ forms a three- to seven-membered heterocyclo    ring with R₁₁, or R₁₂, or R₁₁ forms a three- to seven-membered    heterocyclo ring with R₁₂.

The invention further provides pharmaceutical compositions adapted foruse in treating cGMP-associated conditions comprising a pharmaceuticallyacceptable diluent or carrier and at least one compound of the formula(I) or salt thereof, wherein R₂ and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁ andR₁₂ are as defined above and R₃ is selected from hydrogen and—(CH₂)_(z)Y, with the proviso that at least one of R₂, R₃, R₆, R₇, andR₈ is not hydrogen. The invention further provides methods for treatingcGMP-associated conditions comprising administering to a mammal in needof such treatment a therapeutically-effective amount of one or morecompounds of the formula (I) or salt thereof, wherein R₂ and R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are as defined above and R₃ is selectedfrom hydrogen and —(CH₂)_(z)Y, with the proviso that at least one of R₂,R₃, R₆, R₇, and R₈ is not hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The term “alkyl” refers to straight or branched chain hydrocarbon groupshaving 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkylgroups, that is, alkyl groups of 1 to 4 carbon atoms, are mostpreferred. The term “substituted alkyl” refers to an alkyl group asdefined above having one, two or three substituents selected from thegroup consisting of halo, amino, cyano, hydroxy, alkoxy, alkylthio,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —C(═O)H, —CO₂H, —CO₂-alkyl,cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, or heterocycle.The term “substituted alkyl” also includes an alkyl group as definedabove substituted with N(substituted alkyl) or N(substituted alkyl)₂, orin other words, the groups (CH₂)_(n)NHR′ and (CH₂)_(n)NR′R″, whereineach of R′ and R″ comprises a substituted alkyl or R′ and R″ togetherform a heterocyclo ring.

The term “alkoxy” refers to an alkyl group as defined above bondedthrough an oxygen (—O—). The term “alkylthio” refers to an alkyl groupas defined above bonded through a sulfur (—S—).

The term “cycloalkyl” refers to fully saturated and partiallyunsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atomsas well as such rings having a fused aryl ring such as indan.

The term “substituted cycloalkyl” refers to such rings having one, twoor three substituents, preferably one, selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo,hydroxy, cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —CO₂H,—CO₂-lower alkyl, aryl, heterocyclo, heteroaryl, keto, ═N—OH, ═N—O-loweralkyl, and a five or six membered ketal, i.e. 1,3-dioxolane or1,3-dioxane.

The term “halo” refers to chloro, bromo, fluoro and iodo.

The term “aryl” refers to phenyl, 1-naphthyl and 2-naphthyl, with phenylbeing preferred. The term “aryl” includes such rings having from zero,one, two or three substituents, selected from the group consisting ofalkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro,cyano, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —CO₂H,—(C═O)alkyl, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH₂—CO₂-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,heterocyclo, and heteroaryl.

The term “heterocyclo” refers to substituted and unsubstitutednon-aromatic 3 to 7 membered monocyclic groups, 7 to 11 memberedbicyclic groups, and 10 to 15 membered tricyclic groups which have atleast one heteroatom (O, S or N) in at least one of the rings. Each ringof the heterocyclo group containing a heteroatom can contain one or twooxygen or sulfur atoms and/or from one to four nitrogen atoms providedthat the total number of heteroatoms in each ring is four or less, andfurther provided that the ring contains at least one carbon atom. Thefused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclo ring may contain one, two or three substituents selectedfrom the group consisting of halo, amino, cyano, alkyl, substitutedalkyl, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy, alkylthio,hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,—CO₂H, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl, —(C═O)NH₂,—(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H,—NH—CH₂—CO₂-alkyl, heterocyclo, heteroaryl, keto, ═N—OH, ═N—O-loweralkyl, and a five or six membered ketal, i.e., 1,3-dioxolane or1,3-dioxane.

Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl,imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl.

The term “heteroaryl” refers to substituted and unsubstituted aromatic 5or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and11 to 14 membered tricyclic groups which have at least one heteroatom(O, S or N) in at least one of the rings. Each ring of the heteroarylgroup containing a heteroatom can contain one or two oxygen or sulfuratoms and/or from one to four nitrogen atoms provided that the totalnumber of heteroatoms in each ring is four or less and each ring has atleast one carbon atom. The fused rings completing the bicyclic andtricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain one, two or three substituentsselected from the group consisting of halo, amino, cyano, alkyl,substituted alkyl, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, alkoxy,alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy,phenylthio, —CO₂H, —CO₂-alkyl, cycloalkyl, substituted cycloalkyl,—(C═O)NH₂, —(C═O)NH(alkyl), —(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂,—NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl, heterocylco, and heteroaryl.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “substituted imidazole” refers to an imidazole, an aryl-fusedimidazole such as benzimidazole, or a heteroaryl-fused imidazole such asa pyridoimidazole which contain one or two substituents selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,alkylthio, halo, hydroxy, nitro, cyano, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, —CO₂H, —CO₂-alkyl, cycloalkyl, substitutedcycloalkyl, —(C═O)NH₂, —(C═O)NH(alkyl), —(C═O)NH(cycloalkyl),—(C═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl, phenyl, benzyl,phenylethyl, phenyloxy, phenylthio, heterocyclo, and heteroaryl.

The term “substituted triazole” refers to a triazole having at least onesubstituent selected from the group consisting of alkyl, substitutedalkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano, amino,—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —CO₂H, —CO₂-alkyl, cycloalkyl,substituted cycloalkyl, —(C═O)NH₂, —(C═O)NH(alkyl),—(C═O)NH(cycloalkyl), —(C═O)N(alkyl)₂, —NH—CH₂—CO₂H, —NH—CH₂—CO₂-alkyl,phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, andheteroaryl.

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of the formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as, but not limited to an amine or a pyridine or imidazole ring,and an acidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolation or purification stepswhich may be employed during preparation. Salts of the compounds of theformula I may be formed, for example, by reacting a compound of theformula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

The compounds of formula I which contain a basic moiety, such as, butnot limited to an amine or a pyridine or imidazole ring, may form saltswith a variety of organic and inorganic acids. Exemplary acid additionsalts include acetates (such as those formed with acetic acid ortrihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, ftumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety, such as, butnot limited to a carboxylic acid, may form salts with a variety oforganic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines [formed withN,N-bis(dehydro-abietyl)ethylenediamine], N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g., benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of this invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, and/or a salt and/or solvate thereof. Solvates of thecompounds of formula I are preferably hydrates.

Compounds of the formula I, and salts thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

All stereoisomers of the present compounds, such as those, for example,which may exist due to asymmetric carbons on the R₂ to R₁₂ substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons) and diastereomeric forms, are contemplated andwithin the scope of this invention. Individual stereoisomers of thecompounds of this invention may, for example, be substantially free ofother isomers, or may be admixed, for example, as racemates or with allother or other selected, stereoisomers. The chiral centers of thepresent invention can have the S or R configuration as defined by theIUPAC 1974 Recommendations.

Methods of Preparation

The compounds of the present invention may be prepared by methods suchas those illustrated in the following Schemes I to X. Starting materialsare commercially available or can be readily prepared by one of ordinaryskill in the art using known methods. For all of the schemes andcompounds, the groups R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are as describedabove for a compound of formula I, unless otherwise indicated.

Solvents, temperatures, pressures, and other reaction conditions mayreadily be selected by one of ordinary skill in the art. For example, inthese schemes exemplary hydroxide sources may include sodium hydroxideor lithium hydroxide; an exemplary reducing reagent and inert solvent(for reducing a carboxylic acid or ester group to an alcohol) includeslithium tri-t-butoxyaluminohydride and tetrahydrofuran (THF); exemplarydehydrating/chlorinating agents include POCl₃, PCl₅, SOCl₂ or oxalylchloride; exemplary leaving groups (LG) include triflate, mesylate,tosylate, or halide; and exemplary reagents (for converting a hydroxylgroup to a leaving group) include trifluoromethanesulfonyl chloride,toluenesulfonyl chloride, methanesulfonyl chloride, phosphorusoxychloride, thionyl chloride, and phosphorus pentachloride. Exemplarysolvents, as appropriate, may be selected from 1,2-dichlorobenzene,methylene chloride, dimethylformamide (DMF), alcohols, ethers, includingdiphenyl ether, tetrahydrofuran and dioxane, N,N-dimethylformamide, andacetonitrile, water, mixtures of ethers and water, and the like.

High Speed Analoging (HSA) may be employed in the preparation ofcompounds.

Compounds of formula Ia wherein R₃ is hydrogen can be prepared via thedecarboxylation of a compound of formula Ib in an appropriate degassedinert solvent (e.g., 1,2-dichlorobenzene and diphenyl ether) at elevatedtemperature.

Compounds of formula Ib wherein R₃ is —CO₂H can be prepared by thehydrolysis of compounds of formula Ic using a hydroxide source andappropriate solvent (e.g., water, alcohols, and mixtures of ethers andwater).

Compounds of formula Id wherein R₃ is —CH₂OH can be prepared by reducinga compound of formula Ib or Ic with an appropriate reducing reagent inan inert (reaction) solvent.

Compounds of formula Ic wherein R₃ is —CO₂R₉ can be prepared by reactingcompounds of formula II with an amine of the formula NHR₄R₅. Thereaction may be performed in a solvent as appropriate, such as analcohol, in the presence of an appropriate base, such as triethylamine,and typically under elevated temperatures.

Compounds of formula II can be prepared by reacting compounds of formulaIII with an appropriate dehydrating/chlorinating agent, typically underelevated temperatures.

Compounds of formula III can be prepared from compounds of formula IVvia an intramolecular cyclization typically under elevated temperaturesin an inert solvent, as appropriate, or in neat form.

Compounds of formula IV can be prepared by combining compounds offormula V and VI either neat or in an inert solvent as appropriate,typically under elevated temperatures.

Compounds of formula V and formula VI are either commercially availableor available via methods known to one skilled in the art.

Compounds of formula Ie wherein R₂ is halogen and R₃ is —CH₂OH can beprepared by reducing a compound of formula If or Ig with an appropriatereducing reagent in an inert (reaction) solvent.

Compounds of formula If wherein R₂ is halogen and R₃ is —CO₂H can beprepared by the hydrolysis of compounds of formula Ig using a hydroxidesource in appropriate solvent.

Compounds of formula Ig wherein R₂ is halogen and R₃ is —CO₂R₉(R₉ isother than hydrogen) can be prepared by reacting compounds of formulaVII with an amine of the formula NHR₄R₅ (as in Scheme I for formula Ic).

Compounds of formula VII can be prepared by reacting compounds offormula VIII with an appropriate dehydrating/chlorinating agenttypically under elevated temperatures.

Compounds of formula VIII can be prepared from compounds of formula IXby a condensation with a malonate derivative using base in anappropriate solvent. Sodium alkoxides are exemplary bases and alcoholsexemplary solvents.

Compounds of formula IX are either commercially available or availablevia methods known to one skilled in the art.

Compounds of formula Ih wherein R₃ is —(CH₂)₂OH can be prepared byreducing a compound of formula Ii with an appropriate reducing reagentin an inert solvent.

Compounds of formula Ii wherein R₃ is —CH₂CO₂H can be prepared by thehydrolysis of compounds of formula Ij using a hydroxide source inappropriate solvent.

Compounds of formula Ij wherein R₃ is —CH₂CN can be prepared via thedisplacement of the leaving group (LG) from a compound of formula Xusing an appropriate nucleophile in an inert solvent (e.g., methylenechloride). Nucleophiles may include cyanides from HCN, KCN, or NaCN, ortetrabutylammonium cyanide.

Compounds of formula X can be prepared via reaction of compounds offormula Id or Ie with an appropriate reagent which converts the hydroxylgroup to a leaving group (LG) in an inert solvent (e.g., methylenechloride).

Compounds of formula Id or Ie wherein R₃ is —CH₂OH, can be prepared bythe methods described above in Schemes I and II.

Compounds of formula Ik wherein R₃ is —(CH₂)₃OH can be prepared byreducing a compound of formula Il with an appropriate reducing reagentin an inert solvent.

Compounds of formula Il can be prepared by decarboxylation of compoundsof formula XI at elevated temperature in an inert solvent (e.g., DMF).

Compounds of formula XI can be prepared by the hydrolysis of compoundsof formula Im using a hydroxide source and an appropriate solvent.

Compounds of formula Im wherein R₃ is —CH₂CH(CO₂R₉)₂ can be prepared viathe displacement of the leaving group (LG) from a compound of formula Xusing an appropriate nucleophile (e.g., alkyl malonate) in an inertsolvent (e.g., methylene chloride).

Compounds of formula In wherein R₃ is —(CH₂)_(z)Y can be prepared viathe displacement of the leaving group (LG) from a compound of formula XIusing an appropriate nucleophile in an inert solvent. Exemplarynucleophiles include alcohols of the formula HOR₉, amines of the formulaHNR₁₀R₁₁, mercaptans of the formula HSR₉, cyanides as in Scheme III,imidazole, substituted imidazoles, triazole, and substituted triazoles.

Compounds of formula XII can be prepared via reaction of compounds offormulas Id, Ie, Ih, Ik with an appropriate reagent which converts thehydroxyl group to a leaving group (LG) in an appropriate inert solvent.

Compounds of formulas Id (z=1), Ie (z=1), Ih (z=2), Ik (z=3) can beprepared using the methods described above in Schemes I, II or III.

Compounds of formula Io wherein R₃ is —(CH₂)_(z)(C═O)NR₁₀R₁₁ can beprepared via the aminolysis of an active ester (AE) of formula XIIIusing an amine of the formula NHR₁₀R₁₁ in an inert solvent (e.g.,ethers, described above, and methylene chloride).

Compounds of formula Ip wherein R₃ is —(CH₂)_(z)CO₂R₉ can be preparedvia the esterification of a compound of formula XIII using an alcohol ofthe formula HOR₉, with the alcohol used as solvent or in an inertsolvent such as ethers, described above, or methylene chloride.

Compounds of formula XIII can be prepared via the activation of thecarboxylic acid in compounds of formula Iq using an appropriatecarboxylic acid activating agent in an appropriate solvent. Exemplaryactivating agents include carbonyldiimidazole or dicyclohexylcarbodiimide and pentafluorophenol.

Compounds of formula Iq wherein R₃ is —(CH₂)_(z)CO₂H can be preparedwith the methods described in Schemes III and IV.

Compounds of formula Ir wherein R₃ is —(CH₂)_(z)SO₂NR₁₀R₁₁ can beprepared via the aminolysis of a sulfonyl chloride of formula XIV usingan amine of the formula NHR₁₀R₁₁ in an inert solvent (e.g., ethers ormethylene chloride).

Compounds of formula XIV can be prepared by reacting compounds offormula Is with an appropriate dehydrating/chlorinating agent typicallyunder elevated temperatures.

Compounds of formula Is wherein R₃ is —(CH₂)_(z)SO₂OH can be prepared byoxidation of compounds of formula It.

Compounds of formula It wherein R₃ is —(CH₂)_(z)SH can be prepared bythe methods described above in Scheme IV.

Compounds of formula Iu wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)OR₁₁ can beprepared by reacting compounds of formula Iv with a chloroformate in aninert solvent.

Compounds of formula Iw wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)NR₁₁R₁₂ can beprepared by reacting compounds of formula IX with an alkylating agentunder basic conditions in an inert solvent.

Compounds of formula Ix wherein R₃ is —(CH₂)_(z)NR₁₀(C═O)NHR₁₁ can beprepared by reacting compounds of formula Iv with an isocynate in aninert solvent.

Compounds of formula Iv can be prepared with the methods described abovein Scheme IV.

Compounds of formula Iy wherein R₃ and R₅ form a heterocyclo carboxamidering can be prepared from compounds of formula Iz by hydrolysis anddecarboxylation.

Compounds of formula Iz wherein R₃ and R₅ form a 2-carboxylateheterocyclo carboxamide ring can be prepared from compounds of formulaIaa by a base effected cyclization.

Compounds of formula Iaa wherein R₃ is —CH₂CH(CO₂R₉)₂ and R₅ is hydrogencan be prepared with the methods described in Scheme III.

Compounds of formula Iab wherein R₃ is —(CH₂)_(z)OR₉(OR₁₀)NR₁₁R₁₂ can beprepared from compounds of formula Iac by a base-effected alkylation.

Compounds of formula Iac wherein R₃ is —(CH₂)_(z)OR₉(OH)NR₁₁R₁₂ can beprepared from compounds of formula Iab by an aminolysis of the epoxide.

Compounds of formula Iad wherein R₃ is —(CH₂)_(z)OR₉NR₁₀R₁₁ can beprepared by the method described in Scheme IV.

Compounds of formula Ia wherein R₃ is hydrogen can also be prepared fromcompounds of formula XV by a base-effected alkylation.

Compounds of formula XV can be prepared from compounds of formula XVI bya Curtius rearrangement.

Compounds of formula XVI can be prepared by reacting compounds offormula XVII with an appropriate methyl ketone.

Compounds of formula XVII are either commercially available or availablevia methods known to one skilled in the art.

Preferred Compounds

Preferred compounds of this invention are those of formula (I) and/orpharmaceutically acceptable salts thereof having the followingdefinitions:

wherein,

-   R₂, R₆, and R₇ are independently hydrogen, halogen, alkyl,    substituted alkyl, nitro, cyano, aryl, or heteroaryl;-   R₈ is hydrogen, alkyl, or substituted alkyl, including    —(CH₂)_(n)NR₁₃,R₁₄, wherein R₁₃ and R₁₄ (i) are independently    selected from hydrogen, alkyl, or substituted alkyl, or (ii) taken    together form a heterocylco ring;-   R₃ is —(CH₂)_(z)Y;-   R₄ is hydrogen, lower alkyl, or forms a heterocyclo ring with Y or    R₃;-   R₅ is substituted alkyl;-   R₆ is hydrogen, halogen, trifluoromethyl, nitro, cyano, or aryl;-   Y is (i) independently selected from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,    —O(C═O)NR₁₀R₁₁, —NR₁₀R₁₁, —NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀R₁₁]₂,    —(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₂, —S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole,    substituted imidazole, triazole, substituted triazole, or cyano,    or (ii) taken together with R₄ or R₅, forming a heterocylo ring    therewith;-   m is 0, 1, or 2;-   n is 0, 1, 2, or 3;-   z is 0, 1, 2, or 3;-   R₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,    cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl,    or pentafluorophenyl; and-   R₁₀, R₁₁, and R₁₂ (i) are independently selected from hydrogen,    alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted    cycloalkyl, aryl, heterocyclo, or heteroaryl; or (ii) taken together    wherein R₁₀ with R₁₁ or R₁₂ forms a three- to seven-membered    heterocyclo ring, or R₁₁ with R₁₂ forms a three- to seven-membered    heterocyclo ring.

More preferred are the compounds of formula (I), above, and/orpharmaceutically acceptable salts thereof, wherein

-   R₂ is hydrogen, halogen, lower alkyl, or pyridine;-   R₃ is —(CH₂)_(z)Y;-   R₄ is hydrogen, methyl, or forms a heterocyclo ring with Y or R₃;-   R₅ is substituted alkyl, wherein said substituted alkyl comprises an    aryl, cycloalkyl, or heteroaryl substituent;-   R₆ is hydrogen, halogen, trifluoromethyl, or cyano;-   R₇ is hydrogen or trifluoromethyl;-   R₈ is hydrogen, alkyl, substituted alkyl, or —(CH₂)_(n)NR₁₃,R₁₄,    wherein R₁₃ and R₁₄ (i) are independently selected from hydrogen,    alkyl, or substituted alkyl, or (ii) together form a heterocylco    ring;-   Y is (i) —OR₉, —CO₂R₉, —CH(CO₂R₉)₂, —OR₉NR₁₀R₁₁, —NR₁₀R₁₁,    —(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂, or (ii) together with R₄ forms a    heterocylo ring;-   n is 0, 1, 2, or 3;-   z is 0, 1, 2, or 3;-   R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, or    pentafluorophenyl;-   R₁₀ and R₁₁ are (i) independently selected from hydrogen, alkyl,    substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl,    heterocyclo, or heteroaryl; or (ii) taken together wherein R₁₀ and    R₁₁ forms a three- to seven-membered heterocyclo ring; and-   R₁₂ is aryl, cycloalkyl, or heteroaryl.

Advantageously, R₅ comprises cycloalkyl or an alkyl substituted witharyl. When R₅ is an alkyl substituted with an aryl, advantageously thearyl has one to two substituents wherein at least one of thesubstituents is selected from halogen (e.g., chloro, bromo, fluoro),alkoxy (e.g., methoxy), or a lower alkyl. Advantageously, when R₉comprises a heterocyclo ring with a nitrogen heteroatom, said nitrogenheteroatom has a substituent X₁ selected from lower alkyl, substitutedalkyl, and cycloalkyl. When R₄ and R₃ (or Y) form a heterocyclo ring,said ring advantageously is unsubstituted or has at least onesubstituent X₂ comprising CO₂(alkyl).

Most preferred are the compounds of formula (I) and/or pharmaceuticallyacceptable salts thereof, wherein:

-   R₂ is hydrogen or chloro;-   R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;-   R₄ is hydrogen;-   R₅ is 3-chloro-4-methoxyphenylmethyl;-   R₆ is cyano;-   R₇ is hydrogen;-   R₈ is hydrogen, alkyl, or substituted alkyl;-   Y is —OR₉, —NR₁₀R₁₁, —CO₂R₉, or —(C═O)NR¹⁰R₁₁;-   R₉ is hydrogen, alkyl, or substituted alkyl; and-   R₁₀ and R₁₁ (i) are each independently hydrogen, alkyl, substituted    alkyl, aryl, heterocyclo, or heteroaryl; or (ii) together form a    five- to seven-membered heterocyclo ring.

Preferred Pharmaceutical Compositions for Treating cGMP-AssociatedConditions

Preferred pharmaceutical compositions of this invention are thosecompositions adapted for use in treating cGMP-associated conditionscomprising a pharmaceutically acceptable diluent or carrier and at leastone compound of the formula (I) and/or pharmaceutically acceptable saltsthereof:

wherein,

-   R₂, R₆, and R₇ are independently hydrogen, halogen, alkyl,    substituted alkyl, nitro, cyano, aryl, or heteroaryl;-   R₈ is hydrogen, alkyl, substituted alkyl, or —(CH₂)_(n)NR₁₃,R₁₄,    wherein R₁₃ and R₁₄ (i) are independently selected from hydrogen,    alkyl, or substituted alkyl, or (ii) taken together form a    heterocylco ring;-   R₃ is hydrogen or —(CH₂)_(z)Y;-   R₄ is hydrogen, lower alkyl, or forms a heterocyclo ring with Y or    R₃;-   R₅ is substituted alkyl;-   R₆ is hydrogen, halogen, trifluoromethyl, nitro, cyano or aryl;-   Y is selected (i) independently from —OR₉, —CO₂R₉, —CH(CO₂R₉)₂,    —O(C═O)NR₁₀R₁₁, —NR₁₀R₁₁, —NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀R₁₁]₂,    —(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂, —S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole,    substituted imidazole, triazole, substituted triazole, or cyano,    or (ii) together with R₄ or R₅, forming a heterocylo ring therewith;-   m is 0, 1, or 2;-   n is 0, 1, 2, or 3;-   z is 0, 1, 2, or 3;-   R₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,    cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl,    or pentafluorophenyl; and-   R₁₀, R₁₁, and R₁₂ (i) are independently selected from hydrogen,    alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted    cycloalkyl, aryl, heterocyclo, or heteroaryl; or (ii) taken together    wherein R₁₀ with R₁ or R₁₂ forms a three- to seven-membered    heterocyclo ring, or R₁₁ with R₁₂ forms a three- to seven-membered    heterocyclo ring.

In the pharmaceutical compositions wherein R₃ of formula (I) ishydrogen, it is preferred that R₆ is cyano. In an alternative embodimentwhere R₃ is hydrogen, R₂ advantageously is selected from heteroarylincluding pyridine. Advantageously, when R₃ is hydrogen, R₂ does notinclude hydrogen, chlorine, or methyl.

More preferred pharmaceutical compositions are those including apharmaceutically acceptable diluent or carrier and at least one compoundof the formula (I) and/or pharmaceutically acceptable salts thereof,wherein

-   R₂ is hydrogen, halogen, lower alkyl, or pyridine;-   R₃ is hydrogen or —(CH₂)_(z)Y;-   R₄ is hydrogen, methyl, or forms a heterocyclo ring with Y or R₃;-   R₅ is alkyl substituted with aryl, cycloalkyl, or heterocyclo;-   R₆ is hydrogen, halogen, trifluoromethyl, or cyano;-   R₇ is hydrogen or trifluoromethyl;-   R₈ is hydrogen, alkyl, substituted alkyl, or —(CH₂)_(n)NR₁₃,R₁₄,    wherein R₁₃ and R₁₄ (i) are independently selected from hydrogen,    alkyl, or substituted alkyl, (ii) together form a heterocylco ring;-   Y is (i) —OR₉, —CO₂R₉, —CH(CO₂R₉)₂, —OR₉NR₁₀R₁₁, —NR₁₀R₁₁,    —(C═O)NR¹⁰R₁₁, —NR₁₀(C═O)R₁₂, or (ii) together with R₄ forms a    heterocylo ring;-   n is 0, 1, 2, or 3;-   z is 0, 1, 2, or 3;-   R₉ is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, or    pentafluorophenyl;-   R₁₀ and R₁₁ are (i) independently selected from hydrogen, alkyl,    substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl,    heterocyclo, or heteroaryl; or (ii) taken together wherein R₁₀ and    R₁₁ forms a three- to seven-membered heterocyclo ring; and-   R₁₂ is aryl, cycloalkyl, or heteroaryl.

Advantageously, R₅ comprises an alkyl substituted with cycloalkyl or anaryl group. When R₅ is alkyl substituted with aryl, advantageously thearyl has one to two substituents wherein at least one of thesubstituents is selected from halogen (e.g., chloro, bromo, fluoro),alkoxy (e.g., methoxy), or a lower alkyl. Advantageously, when R₉comprises a heterocyclo ring with a nitrogen heteroatom, said nitrogenheteroatom has a substituent X₁ selected from lower alkyl, substitutedalkyl, and cycloalkyl. When R₄ and R₃ (or Y) form a heterocyclo ring,said ring advantageously is unsubstituted or has at least onesubstituent X₂ comprising CO₂(alkyl).

Most preferred pharmaceutical compositions are those including apharmaceutically acceptable diluent or carrier and at least one compoundof the formula (I) and/or pharmaceutically acceptable salts thereof,wherein

-   R₂ is hydrogen or chloro;-   R₃ is —(CH₂)_(z)Y, wherein z is 0, 1, 2, or 3;-   R₄ is hydrogen;-   R₅ is 3-chloro-4-methoxyphenylmethyl;-   R₆ is cyano;-   R₇ is hydrogen;-   R₈ is hydrogen, alkyl or substituted alkyl;-   Y is —OR₉, —NR₁₀R₁₁, —CO₂R₉, —(C═O)NR₁₀R₁₁;-   R₉ is hydrogen, alkyl, or substituted alkyl; and-   R₁₀ and R₁₁ (i) are each independently hydrogen, alkyl, substituted    alkyl, aryl, heterocyclo, or heteroaryl; or (ii) together form a    five- to seven-membered heterocyclo ring.

Utility

The compounds and compositions of this invention inhibit cGMP PDE, andin particular are potent and selective inhibitors of cGMP PDE 5. Thus,these compounds and compositions are useful in treating cGMP-associatedconditions. A “cGMP-associated condition”, as used herein, denotes adisorder which can be treated by inhibiting cGMP PDE or elevating thelevel of cGMP in a subject, wherein treatment comprises prevention,partial alleviation, or cure of the disorder. Inhibition of cGMP PDE orelevation of the cGMP level may occur locally, for example, withincertain tissues of the subject, or more extensively throughout thesubject being treated for such a disorder. Treatment may be facilitatedwherein elevation of the cGMP level potentiates additional beneficialtherapeutic effects, such as where elevation of the cGMP levelpotentiates the effects of endothelium-derived relaxing factor.

The inventive compounds and compositions are useful for treating avariety of cardiovascular diseases including, but not limited to,hypertension, angina (stable, unstable, and variant), (congestive) heartfailure, restenosis, atherosclerosis, and dyslipidemia, as well asreduced blood vessel patency, thrombus, both venous and arterial,myocardial infarction, peripheral vascular disease, stroke, bronchitis,chronic asthma, allergic asthma, allergic rhinitis, glaucoma, benignprostate hyperplasia (BPH), and forms of cancer responsive to theinhibition of cGMP PDE. In addition, these compounds are useful intreating sexual dysfunction in both men (erectile dysfunction, forexample, due to diabetes mellitus, spinal cord injury, radicalprostatectomy, psychogenic etiology or any other cause) and women byimproving blood flow to the genitalia, especially, the corpuscavernosum. The compounds and compositions of this invention also areuseful in treating diabetes mellitus and related conditions, anddiseases of the gastrointestinal tract, such as those characterized bydisorders of gut motility, including gastric paresis.

The present invention thus provides methods for treating cGMP-associatedconditions, comprising administering to a subject in need thereof aneffective amount of at least one compound of the formula I or a saltthereof, and/or pharmaceutical compositions as described above. Othertherapeutic agents such as those described below may be employed incombination with the compounds of formula I. In the methods of thepresent invention, such other therapeutic agent(s) may be administeredprior to, simultaneously with, or following the administration of theinventive compound(s) and compositions.

The present invention also provides pharmaceutical compositions capableof treating a cGMP-associated condition, as described above. Thecompositions of the present invention may contain other therapeuticagents as described below, and may be formulated, for example, byemploying conventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds and compositions of formula I may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; bucally; parenterally, suchas by subcutaneous, intravenous, intramuscular or intrasternal injectionor infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; rectallysuch as in the form of suppositories; or liposomally; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. These compounds may, for example, be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved by the use of suitable pharmaceuticalcompositions or, particularly in the case of extended release, by theuse of devices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I may also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms that maybe used. Exemplary compositions include those formulating the inventivecompound(s) with fast-dissolving diluents such as mannitol, lactose,sucrose, and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (AVICEL®) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose(SCMC), maleic anhydride copolymer (e.g., GANTREZ®), and agents tocontrol release such as polyacrylic copolymer (e.g., CARBOPOL 934®).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhanceabsorption and/or bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.05 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like, subject to cGMP-associated conditions.

The inventive compounds and compositions may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in treating cGMP-associated conditions such as other cGMP PDEinhibitors, particularly other cGMP PDE 5 inhibitors, modulators of thelarge-conductance calcium-activated potassium (BK) channels,prostanoids, α-adrenergic agonists, endothelin antagonists, angiotensinII (especially, subtype AT₁) antagonists, angiotensin converting enzyme(ACE) inhibitors, renin inhibitors, and serotonin (5-HT_(2c)) agonists.

Exemplary of such other therapeutic agents are the following:phentolamine, yohimbine, papaverine, apomorphine, sildenafil,pyrazolopyrimidinones as described in U.S. Pat. Nos. 5,272,147;5,250,534; 5,426,107; and 5,346,901, quinazolinones as described in U.S.Pat. No. 5,482,941; AT₁ antagonists such as from losartan, irbesartan,valsartan, and candesartan; ET_(A) antagonists such as bosentan,ABT-627, and those described in U.S. Pat. No. 5,612,359 and U.S. patentapplication Ser. No. 60/035,832, filed Jan. 30, 1997; PDE 5 inhibitorsselected from imidazoquinazolines (see WO 98/08848), carbazoles (see WO97/03675, WO 97/03985 and WO 95/19978), imidazopurinones (see WO97/19947), benzimidazoles (see WO 97/24334), pyrazoloquinolines (seeU.S. Pat. No. 5,488,055), quinazolinones as described in U.S. Pat. No.6,087,368, pyridines as described in U.S. patent application Ser. No.60/100,655 filed Sep. 16, 1998, anthranilic acid derivatives (see WO95/18097), fused heterocycles (see WO 98/07430) and thienopyrimidines(see DE 19632423); and 5-HT_(2c) agonists selected from indoles (see J.Med. Chem., 40, 2762-2769 [1997], EP 655440 and EP 657426), andmodulators of the large-conductance calcium-activated potassium (BK)channels as described in U.S. Pat. Nos. 5,565,483 and 5,602,169, and inWO 98/04135 and WO98/23273.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The following assay can be employed in ascertaining the degree ofactivity of a compound as a cGMP PDE inhibitor. Compounds described inthe following Examples have been tested in this assay, and have shownactivity.

PDE Scintillation Proximity Assay Protocol

Sonicated human platelet homogenates are prepared by the method ofSeiler, et al. (Seiler, S., Gillespie, E., Arnold, A. J., Brassard, C.L., Meanwell, N. A. and Fleming, J. S., “Imidazoquinoline Derivatives:Potent Inhibitors of Platelet Camp Phosphodiesterase which Elevate CampLevels and Activate Protein Kinase in Platelets,” Thrombosis Research,62: 31-42 (1991)). PDE 5 is abundant in human platelets, and accountsfor approximately 90% of the cGMP hydrolytic activity in thehomogenates. When necessary, PDE 5 can be resolved from other PDEactivities in the homogenates by anion exchange chromatography on a fastprotein liquid chromatography system (FPLC) using a Mono-Q anionexchange column (Pharmacia) eluted with a linear gradient of 10 mM-450mM NaCl.

The phosphodiesterase activity is assayed using a commercially availablephosphodiesterase [³H]cGMP scintillation proximity (SPA) assay kit(Amersham). The manufacturer's protocol is followed explicitly exceptthat the reactions are carried out at RT and 3 mM nonradioactive cGMP isincluded in the suspension of SPA beads to prevent the synthesis of anyadditional radioactive products.

All documents cited in the present specification are incorporated hereinby reference in their entirety.

The following Examples illustrate embodiments of the inventive compoundsand starting materials, and are not intended to limit the scope of theclaims. For ease of reference, the following abbreviations are used inthe Examples, below:

Abbreviations

-   -   DMSO=dimethylsulfoxide    -   HPLC=high pressure liquid chromatography    -   LRMS=low resolution mass spectrometry    -   mp=melting point    -   tlc=thin layer chromatography    -   RT=room temperature    -   h=hour(s)    -   Ac=acetyl    -   Et=ethyl    -   Me=methyl    -   HOAc=acetate    -   EtOAc=ethyl acetate    -   EDAC.HCl=ethyl-3-(dimethylamino)propyl carbodiimide,        hydrochloride salt    -   HOBT=hydroxybenztriazole    -   NMP=N-methylpyrrolidinone    -   TEA=triethylamine

Preparation of Starting Materials Preparation 1 2-Amino-5-bromo-benyzlalcohol

To 13 mmol of methyl 2-amino-5-bromobenzoate in 20 mL of THF at RT wasadded 65 mmol of 1 M lithium tri-tert-butoxyaluminohydride over 10-15minutes. The solution was heated at reflux for 17 hours. The solutionwas cooled, poured directly onto silica gel, and eluted with methylenechloride/ethyl acetate; 3:1 followed by 1:1. The product was eluted with100% methanol to give 2.59 g of the title compound as an off-whitesolid. MH⁺: 202; LC: 1.09′.

Preparation 2 Diethyl 2-(4-cyanophenylamino)methylenemalonate

To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) was added 10.1g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate (Aldrich,99%), and the mixture was dissolved in 50 mL toluene (HPLC grade). Thesolution was refluxed for four hours with a condensor open to the air.The solution was then poured into 200 mL hexane, and the resulting whiteprecipitate was filtered and washed well with more hexane to yield 10.62g (37.0 mmol, 85% yield) of the title compound as a slightly off-whitesolid (per LC/MS and ¹H NMR). LC [MH⁺] 289, 97% purity.

Preparations 3-6 Diethyl 2-(arylamino)methylenemalonate

Preparations 3-6 of formula (P1) having values for R₆, R₈ listed inTable 1 were prepared by the same method as in preparation 2, using thecorresponding 4 amino-benzene. TABLE 1 Preparation R₆ R₈ 3 Et CN 4 Cl CN5 HOCH₂ Br 6 CO₂CH₃ Br

Preparation 7 Diethyl2-(2-acetoxymethyl-4-bromophenylamino)methylenemalonate

To a solution of 5.83 mmole of product from preparation 5 in 5 ml ofpyridine was added 8.74 mmole of acetic anhydride over 15 minutes andthe mixture stirred at RT for 1.5 hours. Another 8.74 mmole of aceticanhydride were added, and the mixture stirred at RT for 15.5 hours.Another 2.94 mmole of acetic anhydride were added and the mixturestirred at RT for 4 hours. The mixture was poured into water, and anorganic layer extracted with ethyl acetate. The organic layer was washedwith water and saturated NaCl, dried over MgSO₄, and filtered. Thefiltrate was concentrated to give 2.10 g of the title compound as anoff-white solid. MH⁺: 416; LC: 4.25′.

Preparation 8 6-Cyano-4-hydroxyquinoline-3-carboxylic acid ethyl ester

To 100 mL vigorously refluxing diphenyl ether (Aldrich) was added inopen air, in portions over the course of one hour, 10.5 g (36.5 mmol)diethyl 2-(4-cyanophenylamino)methylenemalonate. The solution wasrefluxed for one additional hour. After allowing the solution to cool tobelow 100° C., it was poured into 200 mL hexane. The resultingprecipitate was filtered and washed well with hexane to yield 8.39 g(34.6 mmol, 94%) of the title compound as a light brown solid: MH⁺: 243,mp>265° C.

Preparations 9-12 6,8-Disubstituted 4-hydroxyquinoline-3-carboxylic acidethyl esters

Preparations 9-12 of formula (P2) wherein R₆ and R₈ have the valueslisted in Table 2, were prepared by the same method as in preparation 8,using an appropriately substituted diethyl2-(phenylamino)methylenemalonate. TABLE 2 Preparation R₆ R₈ 9 CN Et 10CN Cl 11 Br AcOCH₂— 12 Br —CO₂CH₃

Preparation 13 4-Chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester

To 9.50 g (39.2 mmol) ethyl 6-cyano-4-hydroxyquinoline-3-carboxylic acidwas added 50 mL POCl₃ (Aldrich, 99%), and the resulting mixture wasrefluxed for 48 hrs. The POCl₃ was evaporated under reduced pressure,and the residue codistilled once with CHCl₃, and twice with toluene. Theresulting brown solid was dissolved in CH₂Cl₂ and treated withtriethylamine until aqueous washings of aliquots had pH>10. The solutionwas then filtered through a 2″ silica pad to yield 10.5 g (40.2 mmol,103% yield) of the title compound as an off-white crystalline solid;MH⁺: 261, 97% purity.

Preparations 14-22 4-Chloroquinoline-3-carboxylic acid ethyl esters

The compounds of formula (P3) were prepared, wherein R₂, R₆, R₇, and R₈have the values listed in Table 3, using the same method as inpreparation 13, with an appropriately-substituted ethyl4-hydroxyquinoline-3-carboxylic acid. TABLE 3 Preparation R₂ R₆ R₇ R₈ 14H CN H Et 15 H CN H Cl 16 H H CF₃ H 17 H CF₃ H H 18 H Br H AcOCH₂ 19 HBr H CO₂CH₃ 20 Cl Br H H 21 Cl CN H H 22 Cl CN H Et

Preparations 23 a) and b) a) Methyl 2-amino-5-cyanobenzoate b) Methyl2-amino-3-ethyl-5-cyanobenzoate

, wherein R₈ is H or Et

A mixture of methyl 2-amino-5-bromobenzoate (4.6 g, 20 mmol), and CuCN(97 g, 22 mmol) in NMP (20 mL) was heated to 190° C. and stirred for 3h. The reaction mixture was poured into a solution of ethylene diamine(4 mL) in H₂O (16 mL) and extracted with toluene (4×20 mL). The combinedextracts were dried (Na₂SO₄). Removal of the solvent gave the titlecompound a) (i.e., R₈ is hydrogen). Use of methyl2-amino-5-bromo-3-ethyl bromobenzoate gave the title compound b) (i.e.,R₈ is ethyl).

Preparations 24 a) and b) a)6-Bromo-2,4-dihydroxylquinoline-3-carboxylic acid ethyl ester b)6-Cyano-2,4-dihydroxylquinoline-3-carboxylic acid ethyl ester

wherein R₆ is Br or CN.

Diethyl malonate was added to a freshly prepared solution of sodiumethoxide in ethyl alcohol. The resulting mixture was stirred for 30 min.To it was then added dropwise a solution of 2-amino-5-bromobenzoic acidmethyl ester in ethyl alcohol. The resultant mixture was refluxedovernight. The ethyl alcohol was removed under reduced pressure, and theresidue was dissolved in water and extracted with EtOAc. The aqueouslayer was acidified with glacial AcOH to pH5. The precipitate wascollected by filtration to yield 2.6 g, (94% yield) the title compounda) (wherein R₆ is Br). Use of 1.76 g (10 mmol) 2-amino-5-cyanobenzoicacid methyl ester yielded 1.7 g (66% yield) of the title compound b)(wherein R₆ is CN).

Preparation 25 6-Cyano-2,4-dihydroxyl-8-ethylquinoline-3-carboxylic acidethyl ester

To a solution of methyl 2-amino-5-cyano-3-ethylbenzoate (1.36 g, 6.2mmol) and TEA (2.6 mL, 18.6 mmol) in THF (50 mL) was added methylmalonyl chloride (1 mL, 9.3 mmol). The mixture was stirred at RT forovernight. Additional TEA (2.6 mL) and methyl malonyl chloride (1 mL)were added, and the reaction was continued for another 24 h. The mixturewas diluted with EtOAc and washed with H₂O and brine. The solvent wasremoved, and the residue was chromatographed (silica gel, EtOAc/hexane,3:7) to give the amide intermediate. NaH (400 mg, 60% oil dispersion)was washed with dry hexane and dried under nitrogen. To it was added asolution of methyl 2-amino-5-cyano-3-ethylbenzoate (1 g, 3 mmol) intoluene (40 mL), which was followed by dropwise addition of EtOH (4 mL).The resultant mixture was refluxed for overnight. The solvent wasremoved and the residue was dissolved in H₂O (insoluable particulateswere removed by filtration). Upon acidification with HOAc, the titlecompound (590 mg) was precipitated out and collected by filtration.

Preparation 26 6-Bromo-2-(2-pyridinyl)quinoline-4-carboxylic acid

To a suspension of 5-bromo isatin (5 g, 20.5 mmol) and 2-acetylpyridine(2.5 g, 20.5 mmol) in aqueous KOH (1.2 g, 33%) was added EtOH until asolution formed. The mixture was refluxed over night. The reactionmixture was neutralized with HOAc (50%) and filtered. The solid wasresuspended in EtOH and filtered to give the title compound (5.5 g). LC:1.66 and MH⁺: 329.

Preparation 27 Azido-6-bromo-2-(2-pyridinyl)quinoline-4-carboxylate

A mixture of 6-bromo-2-(2-pyridine)quinoline-3-carboxylic acid (2.5 g)in SOCl₂ (30 mL) was refluxed for 2 h, and the excess SOCl₂ was removed.The residue was resuspended in acetone (100 mL). To the suspension wasadded a solution of NaN₃ (0.5 g) in water (50 mL) and stirred for 2 h.The solid product was collected by filtration and washed thoroughly withwater, then dried at 40° C. overnight to give the title compound (2.3g). LC: 2.13′.

Preparation 28 6-Bromo-4-tbutoxycarbonylamino-2-(2-pyridinyl)quinoline

A mixture of preparation 27 (2 g) in toluene (50 mL) was refluxed for 3h. Then tBuOH (1 mL) was added and continue to reflux for 2 h. Thereaction mixture was cooled to RT and filtered. The filtrate wasconcentrated to give the title compound (2 g).

EXAMPLE 14-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline-3-carboxylicacid ethyl ester

To 10.0 g (38.4 mmol) 4-chloro-6-cyanoquinoline-3-carboxylic acid ethylester was added 10.4 g (50 mmol, 1.5 eq) 3-chloro-4-methoxybenzyl aminehydrochloride and 35 mL (228 mmol, 6 eq) diisopropylethylamine (Aldrich,99.5+%). The mixture was dispersed in 200 mL n-propanol and brought toreflux for two hours. The solution was then poured into 500 mL water.The resulting precipitate was filtered, then washed with 500 mL water,then twice washed with 50 mL absolute ethanol to yield 14.87 g (37.6mmol, 97% yield) of the title compound as a white fiberous solid aftercodistilling with absolute ethanol: mp: 161-162° C.; LC/MS (M/Z) 396[M+H] observed, 97% purity.

EXAMPLES 2-55 4-Aminoquinoline-3-carboxylic acid ethyl esters

Using the same or similar method of Example 1, compounds having theformula (Iae) were prepared, wherein R₂, R₅, R₆, R₇, and R₈ have thevalues listed in Table 4, starting with corresponding3-carboxylate-4-chloroquinolines and amine hydrochlorides. TABLE 4 HPLCEx. retention No. —R₅ R₂ R₆ R₇ R₈ time (min.) MH⁺ 2

H H CF₃ H 3.63 439 3

Cl Br H H 4.75 437 4

Cl Br H H 4.56 485 5

H CF₃ H H 3.64 439 6

H CN H H 3.73 352 7

H CN H H 3.82 352 8

H F H H 3.41 389 9

H Br H CO₂nPr 3.29 535 10

H Br H CO₂Me 3.52 507 11

H Br H H 2.82 449 12

H CN H Et 2.78 424 13

H CN H Cl 3.89^(b) 430 14

H Br H AcOCH₂ 1.73^(a) 521 15

H Br H Me 3.68 463 16

H CN H Et 1.56^(a) 394 17

H CN H Et 1.68^(a) 428 18

H CN H Et 1.65^(a) 428 19

H CN H Et 1.46^(a) 390 20

H CN H Et 1.73^(a) 380 21

H CN H Et 1.73^(a) 380 22

H CN H CO₂nPr 3.43 482 23

H CN H CO₂Me 3.11 454 24

H CN H CO₂Et 3.27 468 25

H CN H Et 1.23^(a) 350 26

H CN H Et 1.33^(a) 404 27

H CN H Et 1.49^(a) 428 28

H CN H Et 1.38^(a) 396 29

H CN H Et 1.49^(a) 428 30

H CN H Et 1.65^(a) 402 31

H CN H Et 1.70^(a) 416 32

H CN H Et 1.60^(a) 428 33

H CN H Et 1.42^(a) 420 34

H CN H Et 1.39^(a) 420 35

H CN H Et 1.53^(a) 444 36

H CN H Et 1.53^(a) 442 37

H CN H Et 1.28^(a) 550 38

H CN H Et 1.55^(a) 446 39

H CN H Et 1.34^(a) 444 40

H CN H Et 3.54 374 41

H CN H Et 3.55 374 42

H CN H Et 3.94 452 43

H CN H Et 3.95 452 44

H CN H Et 3.78 388 45

H CN H Et 3.77 388 46

H CN H Et 3.26 360 47

H CN H Et 3.65 438 48

H CN H Et 3.53 374 49

H CN H Et 1.38^(a) 426 50

H CN H Et 1.46^(a) 406 51

H CN H Et 1.46^(a) 386 52

H CN H Et 1.80^(a) 442 53

H CN H Et 1.41^(a) 434 54

H CN H Et 1.36^(a) 448 55

H CN H Et 1.52^(a) 424

EXAMPLE 566-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-hydroxymethylquinoline-3-carboxylicacid ethyl ester

A mixture of 1.84 mmole6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-(acetoxymethyl)quinoline-3-carboxylicacid ethyl ester (i.e., Example 14) and 1.84 mmole of potassiumcarbonate in 20 mL of ethanol was stirred at RT for 20 hours. Themixture was concentrated, and the residue was diluted with water andextracted with ethyl acetate. The resultant organic layer was dried overMgSO₄ and filtered, and the filtrate concentrated to give 0.85 g of thetitle compound as a tan solid. MS: 481; LC: 3.43′.

EXAMPLE 576-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(chloromethyl)quinoline-3-carboxylicacid ethyl ester

A solution of 1.73 mmole6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl)amino)-8-hydroxymethylquinoline-3-carboxylicacid ethyl ester (i.e., Example 56) in 8 ml of thionyl chloride wasstirred at RT for 1.5 hours. The solution was concentrated to give 0.86g of the title compound as an orange foam. MS: 499; LC: 4.15′

EXAMPLE 586-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(N,N-dimethylaminomethyl)quinoline-3-carboxylicacid ethyl ester

A solution of 0.20 mmole of example 57 and 2 mmole of 2 M dimethyaminein 1 ml of THF was stirred at RT for 22 hours. An additional 0.25 ml of2 M dimethylamine in THF was added and the solution stirred for 4 hours.The solution was diluted with ethyl acetate and washed with water. Theorganic layer was dried over MgSO₄ and filtered, and the filtrate wasconcentrated. The residue was chromatographed on silica gel eluted withmethylene chloride followed by methylene chloride/ethyl acetate; 95:5and finally with ethyl acetate to give 71 mg of the title compound as abeige solid. MS: 507; LC: 3.71′

EXAMPLE 594-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid

To 8.0 g (20 mmol)4-(3-Chloro-4-methoxyphenylmethylamino)-6-cyanoquinoline-3-carboxylicacid ethyl ester was added 100 mL THF, 100 mL MeOH and 100 mL 1 M NaOH,and the resulting mixture was stirred well. The solids graduallydissolved as the reaction progressed. After 1 h, the THF and most of theMeOH was evaporated under reduced pressure to leave an aqueous slurry ofa white solid. The slurry was acidified to pH 1.5 with HCl, stirred wellfor 1 h, and then filtered and washed well with water to give 7.5 g (20mmol, ˜100% yield) of a white chalky solid. Codistilling twice todryness with absolute ethanol afforded the title compound: LC/MS: M/Z368 (M+H) observed, 90+% purity; mp: decomposed 255-260° C. LC 2.93′.

EXAMPLES 60-644-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acids

Using the same or similar method as described in Example 59, compoundshaving the formula (Iaf) were prepared, wherein R₂, R₆, R₇, and R₈ havethe values listed in Table 5, starting with corresponding3-carboxylatequinolines. TABLE 5 HPLC retention Ex. No. R₂ R₆ R₇ R₈ time(min.) MH⁺ 60 H H CF₃ H 3.67 411 61 Cl Br H H 4.29 455 62 H F H H 3.31361 63 H CN H Et 2.56 396 64 H CN H Cl 3.23 402

EXAMPLE 654-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile

To 2.16 g (5.87 mmol)4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylicacid was added 50 mL diphenyl ether (Aldrich), and nitrogen wasvigorously bubbled through this mixture for 20 minutes. The resultingmixture was then heated to 240° C. under nitrogen for 30 minutes. Duringthe course of the reaction, the dispersed starting material slowlydissolved, and gas evolution was observed. The resulting solution waspoured into 200 mL hexane, and a precipitated solid was filtered toyield 1.43 g (4.42 mmol, 75% yield) of the title compound as a off-whitesolid: LC/MS: M/Z 324 (M+H) observed, 96% purity; mp: decomposed227-230° C. LC: 2.84′.

EXAMPLE 664-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile

The reaction procedure used was similar to that described for Example 65with the following changes: 101 mg (0.255 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid was used to afford 51 mg (57% yield) of the title compound. LC:1.20° M/Z 352 mp: 206-207° C.

EXAMPLE 674-[[(3-Chloro-4-methoxyphenyl)methyl]N-methylamino]-6-quinolinecarbonitrile

To 250 mg4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile(i.e., Example 65) was added 50 mg of NaH, and the mixture was flushedwith nitrogen. 5 mL of DMF was added, and it was stirred for half hour.To the mixture was then added 70 μL of CH₃I, and it was stirred at RT.After 1 hour the reaction was quenched with aqueous NH₄Cl and dilutedwith water, and the precipitate collected by filtration to give (153 mg)of the title compound. LC: 2.48; M/Z 338 m.p. 153-155° C.

EXAMPLE 684-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline-3-carboxylicacid pentafluorophenyl ester

To 275 mg (0.748 mmol) of4-[[(3-chloro-4-methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylicacid was added 276 mg (1.50 mmol, 2.0 eq) pentafluorophenol, and themixture was dispersed in 5 mL anhydrous DMF under nitrogen. To thisdispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) ofdicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate atRT. The resulting mixture was stirred for 18 hours. The reaction wasthen diluted with 10 mL EtAc, and the white precipitate was filtered anddiscarded. The filtrate was concentrated in vacuo, and the residue wastriturated with 5% MeOH/95% CH₂Cl₂ to give 164 mg (0.307 mmol, 41%yield) of the title compound as a white solid: LC/MS: M/Z 534 (M+H)observed, 100% purity; mp: decomposed 215-217° C. LC: 4.15.

EXAMPLE 694-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylicacid pentafluorophenyl ester

The reaction procedure used was similar to that described for Example 68with the following changes: 3.95 g (10.0 mmol)4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethyl-3-quinolinecarboxylicacid was used to afford 2.81 g (5.00 mmol, 50% yield) of the titlecompound as a white solid: mp: 169-170° C.; LC: 2.14^(a); MH⁺ 562.

EXAMPLES 70-1224-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxamides

Compounds having the formula (Iag), wherein R₂, R₆, R₇, R₈, R₁₀, and R₁₁have the values listed in Table 6, were prepared by the followingmethod, starting with corresponding 3-carboxylatequinolines and anappropriate amine:

To 1 eq of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxylic acidpentafluorophenyl ester in THF (approx. 25 mg per 1 mL THF) was added 2eq of an appropriate primary or secondary amine. The resulting reactionwas allowed to stir for 18 hours at RT. The THF was then evaporated invacuo, and the residue was triturated with a 1:1 solution ofether/hexane. The precipitated solid was filtered and washed with 1:1ether/hexane to yield the desired4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarboxamide.Yields were generally >25%. TABLE 6 HPLC Ex. retention No. R₂ R₆ R₇ R₈—NR₁₀R₁₁ time (min.) MH⁺ 70 H H CF₃ H —NH₂ 3.35 410 71 H H CF₃ H

3.09 501 72 H H CF₃ H

3.06 515 73 H H CF₃ H

1.78^(a) 523 74 H H CF₃ H

1.81^(a) 482 75 H H CF₃ H

1.92^(a) 508 76 H H CF₃ H

1.92^(a) 438 77 H H CF₃ H

1.73^(a) 494 78 H CN H H

2.49 458 79 H CN H H

2.56 480 80 H CN H H

2.45 507 81 H CN H H

2.18 450 82 H CN H H —NH₂ 2.73 367 83 H CN H H

2.99 423 84 H CN H H

1.57^(a) 438 85 H CN H H

2.57 410 86 H CN H H

1.47^(a) 503 87 H CN H H

1.91^(a) 478 88 H CN H H

1.55 464 89 H CN H H

1.80 504 90 H CN H H

1.63 494 91 H CN H H

1.64 504 92 H CN H H

1.70 518 93 H CN H Et —NH₂ 2.34 395 94 H CN H Et

2.20 486 95 H CN H Et

2.05 532 96 H CN H Et

1.92 506 97 H CN H H

2.38 478 98 Cl Br H H

3.36 551 99 Cl Br H H

3.38 565 100 Cl Br H H

3.48 591 101 Cl Br H H

3.49 545 102 Cl Br H H

2.74 537 103 Cl Br H H

1.57^(a) 539 104 Cl Br H H

1.52^(a) 594 105 Cl Br H H

1.55^(a) 581 106 Cl Br H H

3.61 579 107 Cl CN H H

3.09 492 108 Cl CN H Et

1.73^(a) 520 109 H CN H Et

1.35^(a) 449 110 H CN H Et

1.21^(a) 532

EXAMPLES 111-1794-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamides

Compounds having the formula (Iah), wherein R₁₀ and R₁₁, have the valueslisted in Table 7, were prepared by the following method:

To a solution of 1.0 eq of the appropriate primary amine or 2.0 eq ofthe appropriate secondary amine in anhydrous THF (3 mL) was added 15 mg4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester (0.028 mmol). Where the amine was ahydrohalide salt, 3 eq of triethylamine were also added. The solutionswere stirred overnight at 50° C., then filtered and purified by SCXcartridges (2 g capacity, p-toluene sulfonic acid) on a Bohdan SPD robot(10 mL MeOH wash, 10 mL 2 M NH₃/MeOH elution). The desired4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxamidewas recovered either by filtration (manual), by concentration of the SCXeluent (by Savant Speedvac), or (if further purification was required)by preparative HPLC (Shimadzu). Average purity: 93% (LC/MS). Averageyield: >25%. TABLE 8 HPLC Ex. retention No. —NR₁₀R₁₁ time (min.)^(a) MH⁺111

1.63 395 112

1.83 423 113

1.96 435 114

2.17 451 115

1.84 439 116

1.70 455 117

1.81 439 118

2.01 467 119

1.97 451 120

1.69 411 121

1.66 425 122

0.64 439 123

1.77 453 124

2.16 453 125

1.78 453 126

1.57 455 127

1.70 465 128

1.78 453 129

1.83 467 130

1.66 452 131

1.77 492 132

1.59 466 133

1.49 466 134

1.49 480 135

1.74 494 136

1.60 464 137

1.66 478 138

1.48 492 139

1.53 424 140

1.53 440 141

1.58 452 142

1.54 452 143

1.58 480 144

1.52 494 145

1.63 506 146

1.59 478 147

1.46 478 148

1.96 522 149

1.73 540 150

1.75 514 151

1.54 466 152

1.63 494 153

1.63 437 154

1.78 453 155

1.66 452 156

1.55 494 157

1.59 437 158

1.59 478 159

1.43 464 160

1.83 435 161

1.59 451 162

1.69 479 163

1.91 507 164

1.63 478 165

1.63 478 166

1.90 493 167

1.43 436 168

1.43 521 169

1.41 480 170

1.64 518 171

1.48 513 172

1.76 514 173

1.45 450 174

1.44 464 175

2.00 457 176

1.61 458 177

1.87 458 178

1.86 487 179

2.25 501

EXAMPLE 1804-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile

To 530 mg (1.0 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylicacid pentafluorophenyl ester was added 15 mL of anhydrous DMF, and theresulting mixture was cooled to 0° C. A solution of 75 mg of NaBH₄ in 5mL of anhydrous DMF was added to the reaction mixture, resulting in aclear red solution with gas evolution. After stirring for 1 hour at 0°C., the reaction was quenched with 2% TFA/MeOH, and the solvent wasremoved under reduced pressure. The oily residue was purified by flashchromatography (silica gel, 3-5% MeOH/CH₂Cl₂) to afford 87 mg (25%yield) of the title compound. LC: 2.60′; MH⁺: 354.

EXAMPLE 1814-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydroxymethyl)-6-quinolinecarbonitrile

To a suspension of 100 mg (0.236 mmol) of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylquinoline-3-carboxylicacid ethyl ester in 2.8 mL anhydrous THF under nitrogen, was added 1.2mL (5.0 eq) of 1 M lithium tri-t-butoxyaluminohydride/THF. The resultingmixture was refluxed overnight with stirring. The reaction was quenchedwith 1 mL of MeOH and partitioned between 75 mL 1 M NaOH and 100 mLCH₂Cl₂. The organic phase was washed with 1 M NaOH (2×30 mL) and driedover MgSO₄. Removal of the solvent under reduced pressure gave 75 mg(84% yield) of the title compound as a light yellow solid. Theanalytical sample was obtained by trituration in ether: mp: 188-189° C.LC: 3.15′; MH⁺: 382.

EXAMPLES 182-190 4-Amino-3-(hydroxymethyl)quinolines

Using the same method of Example 181, compounds having the formula wereprepared, wherein R₅, R₆, and R₈ have the values listed in Table 8,using an appropriate amine (having the group R₅). In Example 190, thereaction was started with 3-ethyl-8-methyldicarboxylatequinoline. TABLE8 HPLC Ex. retention MH⁺ No. —R₅ R₆ R₈ time (min.) Found 182

Br H 2.41 407 183

CN Cl 2.92 388 184

CN Et 1.50^(a) 338 185

CN Et 1.51^(a) 338 186

CN Et 1.45^(a) 386 187

CN Et 1.43^(a) 386 188

CN Et 1.38^(a) 352 189

CN Et 1.25^(a) 348 190

CN —(CH₂)OH 2.59 384

EXAMPLES 191-1943-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

Compounds having the formula (Iaj) were prepared, wherein R₁₀ and R₁₁have the values listed in Table 9, by the following method.

To 70 mg4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrilewas added 5 mL anhydrous CH₂Cl₂ and 70 μL (0.44 mmol, 2.0 eq)diisopropylethytamine, and the resulting solution was cooled to 0° C.under nitrogen. Methanesulfonyl chloride (17 μL, 0.22 mmol, 1.1 eq) wasthen added, and the resulting reaction solution was stirred at 0° C. for30 minutes. The solution was then quenched with 0.24 mmol (1.1 eq) ofthe appropriate amine (having groups R₁₀, R₁₁), and the resultingsolution was stirred for 30 minutes. The solvent was evaporated underreduced pressure and the residue was chromatographed in 5% MeOH/CH₂Cl₂to yield the title compound. TABLE 9 HPLC Ex. retention No. —NR₁₀R₁₂time (min.) MH⁺ 191

2.39 436 192 —NH₂ 1.12 353 193

1.83 444 194

1.84 421

EXAMPLE 1956-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-[(4-methyl-1-piperazinyl)methyl]quinoline

To4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-bromoquinolinewas added SOCl₂, and the resulting reaction solution was stirred at RTunder nitrogen for 30 minutes. The SOCl₂ was then evaporated underreduced pressure, and the residue was left overnight under high vacuum.The yellow residue was redissolved in anhydrous DMF, and this solutionwas then added to a solution of N-methylpiperazine in anhydrous THF. Theresulting reaction solution was stirred for 6 hours at RT, by which timeHPLC showed the reaction to be complete. After evaporating the solvent,the crude product was chromatographed in 3% MeOH/CH₂Cl₂ to yield thetitle compound. LC: 2.12′; MH⁺: 489

EXAMPLES 196-2243-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

Compounds having the formula (Iak) were prepared, wherein values for R₂,R₈, R₁₀ and R₁₁ are as in Table 10, using the same or similar method asin Example 195, starting with the corresponding4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-quinolinecarbonitrile.TABLE 10 HPLC retention time MH⁺ Ex. No. —NR₁₀R₁₁ R₂ R₈ (min.) Found 196

H H 2.55 437 197

H H 3.43 465 198

Cl H 1.43^(a) 471 199

H H 2.40 381 200

H H 2.43 449 201

H H 1.96 437 202

H H 2.21 435 203

H H 2.24 451 204

H H 1.81 437 205

H H 1.60 423 206

H H 1.97 451 207

H H 2.33 435 208

H H 2.61 435 209

H H 1.86 423 210

H H 2.74 449 211

H H 2.25 451 212

H H 1.17^(a) 437 213

H H 2.80 477 214

H H 2.50 461 215

H H 2.45 473 216

H Et 1.34^(a) 465 217

H H 2.40 443 218

H Et 1.27^(a) 465 219

H Cl 1.20^(a) 457 220

H Cl 1.23^(a) 485 221

H Cl 1.35^(a) 457 222

H Et 1.20^(a) 451 223

H Et 1.45^(a) 479 224

H Et 1.45^(a) 479

EXAMPLES 225-2633-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

Compounds of formula (Ial) were prepared, wherein R₁₀ and R₁₁ have thevalues listed in Table 10, with the following method (Automated parallelsynthesis).

A mixture of 1 eq. of4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-chloromethyl-6-cyanoquinolineand 3 eq. of an appropriate amine in THF was reacted for the overnightat RT. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was dissolved in CH₂Cl₂ and washed with H₂O,then dried. Removal of the solvent gives the product. TABLE 11 HPLCretention Ex. No. —NR₁₀R₁₁ time (min.) MH⁺ 225

2.54 407 226

2.65 421 227

2.82 435 228

2.99 420 229

2.42 411 230

2.83 438 231

2.4 393 232

2.46 407 233

2.92 423 234

3.18 438 235

2.76 435 236

2.48 395 237

2.42 411 238

2.99 437 239

2.73 423 240

2.8 423 241

3.28 435 242

2.84 423 243

2.44 381 244

2.5 410 245

2.4 397 246

3.07 437 247

2.91 423 248

2.55 395 249

2.44 395 250

2.55 409 251

2.64 409 252

2.56 406 253

3 423 254

2.65 425 255

2.54 409 256

3.09 437 257

2.44 411 258

2.43 410 259

2.61 409 260

2.61 409 261

2.64 437 262

2.71 425 263

2.63 437

EXAMPLES 264-2663-(N-acylaminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitriles

Compounds of formula (Iam) were prepared, wherein R₁₂ has the values inTable 12, below. To a mixture of acyl chloride and triethylamine inCH₂Cl₂ was added a solution of3-aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbonitrile(i.e., Example 192) in dioxane. The reaction mixture was stirred at RTfor 1 h. Then the mixture was diluted with EtOAc and washed with waterbrine and dried (MaSO₄). The solvent was removed under reduced pressureand the residue was subjected to flash column chromatography (silicagel, CH₂Cl₂/MeOH, 10:1) to give the compounds of Table 12. TABLE 12 HPLCEx. retention No. R₁₂ time (min.) MH⁺ 264

2.76 457 265

3.00 463 266

2.50 458

EXAMPLES 267-2833-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]quinolines

Compounds of formula (Ian) were prepared, wherein R₂, R₆ R₈, and R₉ havethe values listed in Table 13, with the following method.

To4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl)-6-bromoquinolinewas added SOCl₂, and the resulting reaction solution was stirred at RTunder nitrogen for 30 minutes. The SOCl₂ was then evaporated underreduced pressure, and the residue was left overnight under high vacuum.The yellow residue was redissolved in anhydrous DMF, and this solutionwas then added to a solution of appropriate alcohol in anhydrous THF (orthe yellow residue was treated directly with an appropriate liquidalcohol). The resulting reaction solution was stirred for 6 hours atelevated temperature, by which time HPLC showed the reaction to becomplete. After evaporating the solvent, the crude product waschromatographed to yield the title compound. TABLE 13 HPLC Ex. retentionNo. —R₉ R₂ R₆ R₈ time (min.) MH⁺ 267

H CN Et 1.69^(a) 424 268 —CH₃ H CN Et 3.10 396 269

H CN Et 3.35 466 270

H CN Et 3.42 424 271

H CN Et 3.29 410 272

H CN Et 1.60^(a) 454 273

H CN Et 1.39^(a) 426 274

H CN Et 3.91 565 275

H CN Et 3.91 565 276

H CN Et 3.80 551 277

H Br H 2.78 435 278

Cl CN H 2.13^(a) 571 279

Cl CN Et 2.37^(a) 599 280 CH₃ H Br ClCH₂ 3.55 469 281

H Br ClCH₂ 3.78 497 282

H CN Et 3.18 438 283 CH₃ H CN ClCH₂ 3.17 439

EXAMPLES 284-2884-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-[[[(2S)-2-pyrrolidinyl]methoxy]methyl]-6-quinolinecarbonitriles

Compounds of formula (Iao) were prepared, wherein R₂ and X₁ have thevalues listed in Table 14, with the methods set forth below.

EXAMPLE 284

Example 275 was treated with TFA/CH₂Cl₂ (1:1) for 2 hours. The reactionmixture was concentrated. The residue was treated with NaHCO₃ (aq. 10%)and extracted with CH₂Cl₂. The combined extracts were dried (NaSO₄) andthe solvent was removed. The residue was then purified by preparativeHPLC to give Example 284.

EXAMPLE 285

The same method as Example 285 was used, starting with Example 279.

EXAMPLE 286

To a solution of Example 284 (30 mg) in THF was added triethylamine (28μL) which was followed by CH₃I (4.5 μL). The resultant mixture wasstirred at RT for overnight. The solvent was removed and the residue waschromatographed (silica gel, CH₃OH/CHCl₃, 1:9) to give Example 286 (5.1mg).

EXAMPLES 287 & 288

To a solution of 0.127 mmole of Example 284 and 1.27 mmole of the ketonein 0.5 mL of methanol cooled in an ice bath was added 0.635 mmole ofsodium cyanoborohydride. The ice bath was removed and the suspensionstirred for 4 hours to 2 days. The solution was acidified withconcentrated HCl and allowed to stir for a few minutes. The solution wasneutralized with concentrated NH₄OH and extracted with methylenechloride. The organic layer was dried over MgSO₄ and filtered, and thefiltrate concentrated. The residue was chromatographed on silica geleluted with methylene chloride/methanol; 95:5 and 9:1 to give Examples287 and 288. TABLE 14 HPLC retention time Ex. No. R₂ X₁ (min) MH⁺ 284 HH 1.27^(a) 465 285 Cl H 1.83^(a) 499 286 H —CH₃ 1.27^(a) 479 287 H

2.72 533 288 H —CH(CH₃)₂ 2.57 507

EXAMPLES 289-2968-Aminomethyl-3-alkoxymethyl-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]quinolines

Compounds having the formula (Iap) were prepared, wherein R₆, R₉, R₁₃and R₁₄ have the values listed in Table 15. A solution of 0.072 mmole of8-chloromethyl quinoline and 0.072 mmole of amine in 0.5 mL of THF wasstirred at RT for 16 hours. Another 0.144 mmole of amine were added tothe incompleted reactions and the solution stirred for 24 hours. Thesolution was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water, dried over MgSO₄, and filtered, andthe filtrate was concentrated. The residue was chromatographed on silicagel eluted with methylene chloride/methanol; 98:2, 95:5 followed bymethylene chloride/methanol/NH₄OH; 90:9:1, to give the products. TABLE15 HPLC retention time Ex. # —R₉ R₆ —NR₁₃R₁₄ (min.) MH⁺ 289 —CH(CH₃)₂ Br

1.54^(a) 506 290 —CH(CH₃)₂ Br —NHCH₃ 1.47^(a) 492 291 —CH₃ CN

2.81 425 292 —CH₃ CN

2.15 480 293 —CH₃ CN

1.60 468 294 —CH₃ CN

2.30 508 295 —CH₃ CN

1.62 494 296 —CH₃ CN

1.62 508

EXAMPLES 297-2993-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitriles

Compounds having the formula (Iaq) were prepared, wherein R₉ issubstituted alkyl comprising CH₂CH(OH)CH₂NR₁₀R₁₁, and R₁₀ and R₁₁ havethe values listed in Table 16. A solution of 0.11 mmole of Example 282and 0.22 mmole of the appropriate amine in 1 mL of propanol was heatedat 60-70° C. for 45 minutes to 30 hours. The solution was concentratedand the residue chromatographed (silica gel, methylenechloride/methanol; 95:5, 9:1 and 4:1) to give the products. TABLE 16HPLC Ex. retention No. —NR₁₀R₁₁ time (min.) MH⁺ 297

2.51 509 298

2.67 539 299

2.48 483

EXAMPLE 3003-[[3-[Bis(1-methylethyl)amino]-2-methoxypropoxy]methyl]-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-6-quinolinecarbonitrile

To 0.069 mmole of Example 298 in 0.5 ml of DMF cooled in an ice bath wasadded 0.072 mmole of 60% NaH in mineral oil. The ice bath was removed,the suspension stirred for 90 minutes, and 0.076 mmole of iodomethanewere added. The solution was stirred at RT for 16 hours. An additional0.038 mmole of 60% NaH in mineral oil and 0.038 mmole of iodomethanewere added and the solution stirred for 4 hours. The solution wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with water and saturated NaCl solution, dried over MgSO₄ andfiltered, and the filtrate concentrated. The residue was chromatographedon silica gel eluted with methylene chloride/methanol; 95:5 to give 19mg of the title compound as a colorless oil. MH⁺: 553; LC: 3.21′.

EXAMPLES 301 AND 302[[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinyl]methyl]propanedioicacid dialkyl ester

Compounds having the formula (Iar) were prepared, wherein R₈ and R₉ havethe values listed in Table 17. To a dry clean reaction flask was charged1.3 g (33 mmole) of sodium hydride (60% in mineral oil) and 160 ml ofdry THF. To this mixture was added dropwise 6.5 g (30 mmole) ofdi-t-butylmalonate over a period of 20 minutes at RT. After completionof the addition, the reaction mixture was stirred at RT for anadditional 15 minutes then cooled to −78° C. A solution of the3-chloromethyl quinoline (˜10 mmole) in 160 ml of DMF was added via anaddition funnel over a period of 1 hour. After completion of theaddition, the reaction mixture was stirred at −78° C. for one more hourthen was quenched with water at 0° C. THF was removed under reducedpressure. The resulting solution was diluted with ethyl ether washedwith water three times, brine, dried over sodium sulfate, andconcentrated, and then purified by column chromatograph (silica gelCH₂Cl₂/MeOH, 100:5) to give the product (2.75 g). TABLE 17 HPLCretention Ex. No. R₈ R₉ time (min.) MH⁺ 301 H t-butyl 3.19 552 302 Et Me3.22 496

EXAMPLE 3034-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinepropanoicacid

Example 301 (200 mg) was dissolved in 10 ml of ethanol. 1 ml of 10%LiOH/H₂O aqueous solution was added. The reaction solution was stirredat 45° C. for 2 hours. Ethanol was removed under reduced pressure. Theresulting aqueous solution was adjusted to pH=4 with 10% HCl. The solidwas collected by filtration, rinsed with water, dried to afford 160 mgslightly yellow solid. This product (300 mg) was mixed in 0.3 ml of DMFand stirred at 130° C. for 10 minutes. The reaction mixture was cooledto room temperature. Water was added. The solid was collected byfiltration, rinsed with water, and dried to afford 244 mg of the titlecompound. LC: 2.20′, MH⁺: 396

EXAMPLES 304-3061-[(3-Chloro-4-methoxyphenyl)methyl]-1,2,3,4-tetrahydro-2-oxobenzo[h]-1,6-naphthyridine-9-carbonitriles

Compounds having the formula (Ias) wherein R₈ and X₂ have the valueslisted in Table 18, were prepared as follows.

EXAMPLES 304-305

To a suspension of NaH (123 mg) in THF (10 mL) was addeddimethylmalonate (370 mg) dropwise. The mixture was stirred at RT for 15min. then cooled to −78° C. A solution of4-(3-chloro-4-methoxyphenylmethylamino)-3-chloromethyl-6-cyanoquinoline(0.85 mmol) in DMF was then added dropwise. The reaction was quenched atlow temperature and diluted with Et₂O then washed with water. The etherlayer was concentrated and the residue was purified by flash column(silica gel, CH₂Cl₂/MeOH, 100:4) to give example 303 (160 mg).

EXAMPLE 306

A mixture of the compound of Example 305 (20 mg), 1-isopropylpypirizine(13 mg), EDAC.HCl (20 mg), HOBT.H₂O (15 mg) and DMAP (trace) in pyridine(1.5 mL) was stirred at RT for over night. The crude product waspurified by preparative HPLC to give Example 306. TABLE 18 HPLCretention Ex. No. R₈ —X₂ time (min.) MH⁺ 304 H —(C═O)OCH₃ 2.91 436 305Et —(C═O)OCH₃ 4.04 464 306 H H 2.79 378

EXAMPLES 307-3144-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-alkyl-3-quinolinepropanamides

Compounds of formula (Iat) wherein R₁₀ and R₁₁ have the values listed inTable 19, were prepared as follows.

The compound of Example 303 (20 mg, 0.05 mmole) was mixed with BOPreagent (44 mg, 0.1 mmole) in 3 ml of pyridine and stirred at RT for 3hours. The resulting reaction mixture was purified by preparative HPLCto afford a cream-colored solid. TABLE 19 HPLC Ex. retention No.—NR₁₀R₁₁ time (min.) MH⁺ 307

2.16 486 308 NH₃ 2.08 395 309

2.22 478 310

2.34 423 311

2.14 506 312

2.66 463 313

2.91 477 314

2.71 463

EXAMPLE 3156-Bromo-N-[(3-chloro-methoxyphenyl)methyl]-2-(2-pyridinyl)-4-quinolinamine

To a suspension of 6-bromo-2-(2-pyridine)quinoline-3-aminotbutyl ester(preparation 28) (300 mg) in DMF (10 mL) was added a solution of HMDSNain THF (1 M, 0.9 mL) at RT to generate a brown solution. Then3-chloro-4-methoxybenzyl chloride (160 mg) was added. The reactionmixture was stirred at RT for 2 h. An additional solution of HMDSNa inTHF (0.9 mL) and 3-chloro-4-methoxybenzyl chloride (2 eq.) was added andcontinue to stir. When the starting material was consumed, the reactionmixture was treated with TFA. Removal of the solvent and the residue wasredissolved in EtOAc and washed with 1 N NaOH and water. Removal of thesolvent an tritrated with Et₂O to give the title compound (163 mg) as alight yellow solid. LC: 1.73′ MH⁺: 454.

1. A compound of the formula:

or a pharmaceutically-acceptable salt thereof, wherein: R₅ iscycloalkyl, substituted cycloalkyl, aryl or heteroaryl; Y is selectedfrom —O(C═O)NR₁₀R₁₁, —NR₁₀R₁₁, —NR₁₀(C═O)NR₁₁R₁₂, —CH[(C═O)NR₁₀R₁₁]₂,—(C═O)NR₁₀R₁₁, —NR₁₀(C═O)R₁₂, —S(O)_(m)R₉, —SO₂NR₁₀R₁₁, imidazole,substituted imidazole, triazole, substituted triazole, or cyano, or (ii)together with one of R₄ and R₅ to form a heterocylo ring therewith; andR₉ is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl,substituted cycloalkyl, heterocyclo, aryl, heteroaryl orpentafluorophenyl; R₁₀, R₁₁, and R₁₂ are (i) independently selected fromhydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substitutedcycloalkyl, aryl, heterocyclo and heteroaryl; or (ii) taken together,wherein R₁₀ forms a three- to seven-membered heterocyclo ring with R₁₁or R₁₂, or R₁₁ forms a three- to seven-membered heterocyclo ring withR₁₂; R₂ is hydrogen, halogen, C₁₋₄alkyl or C₁₋₄haloalkyl; R₆ and R₇ areselected from hydrogen, halogen, C₁₋₄alkyl, trifluoromethyl, alkoxy,nitro, and cyano; R₈ is hydrogen, alkyl, substituted alkyl, or CO₂alkyl;m is 0, 1 or 2; and z is 0, 1, 2 or
 3. 2. A compound of claim 1 or apharmaceutically-acceptable salt thereof, wherein Y is —NR₁₀R₁₁ or—(C═O)NR₁₀R₁₁; and R₁₀ and R₁₁ are (i) independently hydrogen, alkyl,substituted alkyl, cycloalkyl, alkoxy, or heterocyclo, or (ii) togetherform a heterocylco ring.
 3. The compound of claim 1, wherein R₆ iscyano.
 4. A pharmaceutical composition adapted for treating acGMP-associated condition comprising one or more compounds of theformula of claim
 1. 5. A method of treating a cGMP-associated conditioncomprising administering to a mammal in need thereof atherapeutically-effective amount of one or more compounds of claim
 1. 6.The method of claim 5, wherein the cGMP-associated condition is selectedfrom a cardiovascular disorder, male or female sexual dysfunction,diabetes mellitus, and a gastrointestinal disorder comprising gastricparesis.